Department of pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China; CiXi Biomedical Research Institute of Wenzhou Medical University, China.
Department of pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China; CiXi Biomedical Research Institute of Wenzhou Medical University, China.
J Control Release. 2022 Oct;350:93-106. doi: 10.1016/j.jconrel.2022.08.018. Epub 2022 Aug 17.
Diabetic foot ulcer (DFU) is a devastating complication in diabetes patients, imposing a high risk of amputation and economic burden on patients. Sustained inflammation and angiogenesis hindrance are thought to be two key drivers of the pathogenesis of such ulcers. Nitric oxide (NO) has been proven to accelerate the healing of acute or chronic wounds by modulating inflammation and angiogenesis. However, the use of gas-based therapeutics is difficult for skin wounds. Herein, therapeutic NO gas was first prepared as stable microbubbles, followed by incorporation into a cold Poloxamer-407 (P) solution. Exposed to the DFU wound, the cold P solution would rapidly be transformed into a semisolid hydrogel under body temperature and accordingly capture NO microbubbles. The NO microbubble-captured hydrogel (PNO) was expected to accelerate wound healing in diabetic feet. The NO microbubbles had an average diameter of 0.8 ± 0.4 μm, and most of which were captured by the in situ P hydrogel. Moreover, the NO microbubbles were evenly distributed inside the hydrogel and kept for a longer time. In addition, the gelling temperature of 30% (w/v) P polymer (21 °C) was adjusted to 31 °C for the PNO gel, which was near the temperature of the skin surface. Rheologic studies showed that the PNO gel had mechanical strength comparable with that of the P hydrogel. The cold PNO solution was conveniently sprayed or smeared on the wound of DFU and rapidly gelled. In vivo studies showed that PNO remarkably accelerated wound healing in rats with DFU. Moreover, the sustained inflammation at the DFU wound was largely reversed by PNO, as reflected by the decreased levels of proinflammatory cytokines (IL-1β, IL-6 and TNF-α) and the increased levels of anti-inflammatory cytokines (IL-10, IL-22 and IL-13). Meanwhile, angiogenesis was significantly promoted by PNO, resulting in rich blood perfusion at the DFU wounds. The therapeutic mechanism of PNO was highly associated with polarizing macrophages and maintaining the homeostasis of the extracellular matrix. Collectively, PNO gel may be a promising vehicle of therapeutic NO gas for DFU treatment.
糖尿病足溃疡（DFU）是糖尿病患者的一种严重并发症，会增加患者截肢和经济负担的风险。持续的炎症和血管生成障碍被认为是这种溃疡发病机制的两个关键驱动因素。一氧化氮（NO）已被证明通过调节炎症和血管生成来加速急性或慢性伤口的愈合。然而，气体基疗法在皮肤伤口上的应用较为困难。在此，研究人员首次将治疗性 NO 气体制备成稳定的微泡，然后将其纳入冷泊洛沙姆 407（P）溶液中。在 DFU 伤口处，冷 P 溶液在体温下会迅速转化为半固体水凝胶，并相应地捕获 NO 微泡。捕获 NO 微泡的水凝胶（PNO）有望加速糖尿病足的伤口愈合。NO 微泡的平均直径为 0.8±0.4μm，其中大部分被原位 P 水凝胶捕获。此外，NO 微泡在水凝胶内均匀分布且保持时间更长。此外，将 30%（w/v）P 聚合物（21°C）的凝胶温度调整至 31°C 以用于 PNO 凝胶，这接近皮肤表面的温度。流变学研究表明，PNO 凝胶具有与 P 水凝胶相当的机械强度。冷 PNO 溶液可方便地喷涂或涂抹在 DFU 伤口上，并迅速凝胶。体内研究表明，PNO 显著加速了糖尿病足大鼠的伤口愈合。此外，PNO 大大逆转了 DFU 伤口处的持续炎症，反映为促炎细胞因子（IL-1β、IL-6 和 TNF-α）水平降低和抗炎细胞因子（IL-10、IL-22 和 IL-13）水平升高。同时，PNO 显著促进了血管生成，导致 DFU 伤口处的血液灌注丰富。PNO 的治疗机制与极化巨噬细胞和维持细胞外基质平衡密切相关。综上所述，PNO 凝胶可能是治疗 DFU 的治疗性 NO 气体的一种有前途的载体。
